title: Design, synthesis, and biological evaluation of novel 2-ethyl-5-phenylthiazole-4-carboxamide derivatives as protein tyrosine phosphatase 1B inhibitors with improved cellular efficacy.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is implicated as a key negative regulator of the insulin and leptin signal-transduction pathways. PTP1B inhibitors have emerged as attractive and potent pharmaceutical agents for the treatment of type 2 diabetes and obesity. We identified a series of 2-ethyl-5-phenylthiazole-4-carboxamide (PTA) derivatives, inspired from the ACT scaffold of Scleritodermin A, as a novel class of PTP1B inhibitors. Structure-activity relationship (SAR) analysis and docking studies revealed the molecular basis of PTP1B inhibition by these compounds. PTA derivative 18g was capable of inhibiting intracellular PTP1B and subsequently activating the insulin signaling pathway. Treatment of cells with 18g markedly increased the phosphorylation levels of IRβ and Akt as well as the rate of glucose uptake.
authors.affiliation: Chinese National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 189 Guoshoujing Road, Zhangjiang Hi-Tech Park, Shanghai 201203, People's Republic of China.
authors.forename: Yue-Ting
authors.initials: YT
authors.lastname: Chen
authors.forename: Chun-Lan
authors.initials: CL
authors.lastname: Tang
authors.forename: Wei-Ping
authors.initials: WP
authors.lastname: Ma
authors.forename: Li-Xin
authors.initials: LX
authors.lastname: Gao
authors.forename: Yi
authors.initials: Y
authors.lastname: Wei
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Jing-Ya
authors.initials: JY
authors.lastname: Li
authors.forename: Jia
authors.initials: J
authors.lastname: Li
authors.forename: Fa-Jun
authors.initials: FJ
authors.lastname: Nan
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D008958:Models, Molecular; D015394:Molecular Structure; D010766:Phosphorylation / Q000187:drug effects; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D013844:Thiazoles; D051057:Proto-Oncogene Proteins c-akt; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1
keywords: 2-Ethyl-5-phenylthiazole-4-carboxamide (PTA); Protein tyrosine phosphatase 1B; SAR; Type 2 diabetes